Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced transcription coactivator hnRNAP2 acetylates Lys 8 of H4 through an intrinsic histone lysine acetyltransferase (KAT) activity with Arg 48 and Arg 50 of hnRNAP2 being essential for acetyl-CoA binding and acetyltransferase activity. H4K8 acetylation at the mitochondrial stress-responsive promoters by hnRNAP2 is essential for transcriptional activation. We found that the previously described mitochondria-to-nucleus retrograde signaling-mediated transformation of C2C12 cells caused an increased expression of genes involved in various oncogenic processes, which is retarded in hnRNAP2 silenced or hnRNAP2 KAT mutant cells. Taken together, these data show that altered gene expression by mitochondria-to-nucleus retrograde signaling involves a novel hnRNAP2-dependent epigenetic mechanism that may have a role in cancer and other pathologies.

中文翻译：

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HnRNPA2 是一种新型组蛋白乙酰转移酶，可介导线粒体应激诱导的核基因表达。

线粒体 DNA 拷贝数减少、线粒体 DNA 突变或电子传递链复合物破坏会诱导线粒体到细胞核的逆行信号传导，从而诱导核基因表达的整体变化，最终导致包括癌症在内的各种人类病理。最近的研究表明，这些线粒体变化会导致核基因的转录重编程，尽管这种串扰的机制仍不清楚。在这里，我们提供证据表明线粒体到细胞核的逆行信号传导通过异源核糖核蛋白 A2 (hnRNAP2) 调节染色质乙酰化并改变核基因表达。当线粒体 DNA 含量恢复到接近正常细胞水平时，这些过程就会逆转。我们发现，线粒体应激诱导的转录共激活因子 hnRNAP2 通过内在的组蛋白赖氨酸乙酰转移酶 (KAT) 活性乙酰化 H4 的 Lys 8，其中 hnRNAP2 的 Arg 48 和 Arg 50 对于乙酰辅酶 A 结合和乙酰转移酶活性至关重要。hnRNAP2 对线粒体应激反应启动子的 H4K8 乙酰化对于转录激活至关重要。我们发现，先前描述的线粒体到细胞核逆行信号介导的 C2C12 细胞转化导致参与各种致癌过程的基因表达增加，而在 hnRNAP2 沉默或 hnRNAP2 KAT 突变细胞中，这种表达被抑制。总而言之，这些数据表明，线粒体到细胞核逆行信号传导改变的基因表达涉及一种新的 hnRNAP2 依赖性表观遗传机制，该机制可能在癌症和其他病理学中发挥作用。